Biomedical subjects

Joseph W Harding

Publications and source records attributed to Joseph W Harding.

17 recordsLinked to original sources

PubMed2006

Habituation of the head-shake response induces changes in brain matrix metalloproteinases-3 (MMP-3) and -9.

Habituation is defined as a decrease in responsiveness to a repeatedly presented stimulus. The head-shake response (HSR) demonstrates several fundamental properties of habituation including sensitivity to the frequency and intensity of stimulation, and spontaneous recovery. This response shows behavioral plasticity; however the neural plasticity presumed to underlie this behavioral phenomenon has only recently been investigated. The present study initially compared male and female rats and noted equivalent habituation and spontaneous recovery. A second experiment utilized female rats to test the hypothesis that habituation induces changes in neural plasticity. At inter-session intervals (ISIs) of 5 min, 2, 6, and 24 h following HSR habituation independent groups of rats received a second habituation experience, then tissue samples were immediately collected from hippocampal, prefrontal and piriform cortices, and cerebellum. Western blots indicated significant elevations in the expression of matrix metalloproteinase-3 (MMP-3) in hippocampal, prefrontal and piriform cortices at a delay interval of 2 h, and in the prefrontal cortex at 24 h in habituated rats. Increases in active and pro MMP-9 activity were measured by zymography in the hippocampus of habituated rats over yoked controls. Decreases in active MMP-9 activity were seen in the prefrontal cortex, and in pro MMP-9 in the piriform cortex, of habituated as compared with yoked control rats. No changes in MMP-3 or MMP-9 were observed in the cerebellum, and no changes in MMP-2 were seen in any of the four structures examined. These results suggest that habituation of the HSR produced elevations in MMP-3 expression in three of the four structures presently examined, accompanied by increased MMP-9 activity in the hippocampus and decreases in the prefrontal cortex. However, cues present in the test environment appear to have provoked elevations in MMP-3 and -9 independent of those accompanying habituation.

Analysis of Variance↗

PubMed2006

REM sleep deprivation attenuates actin-binding protein cortactin: a link between sleep and hippocampal plasticity.

Rapid eye-movement sleep (REMS) is thought to affect synaptic plasticity. Cortactin is a cytoskeletal protein critically involved in the regulation of actin branching and stabilization including the actin backbone of dendritic spines. Hippocampal cortactin levels, phosphorylation, and processing appear to be altered during learning and long-term potentiation (LTP); consistent with a role for cortactin in the dendritic restructuring that accompanies synaptic plasticity. In this study juvenile male Sprague-Dawley rats were selectively REMS-deprived (RD) for 48 h by the flowerpot method. Cage control (CC) and large pedestal control (PC) animals were used for comparison. Animals were euthanized immediately, or 12 h, after removal from the pedestal. The hippocampus was dissected, flash-frozen, and stored for subsequent Western blot or quantitative RT-PCR analysis of cortactin. Cortactin mRNA/cDNA levels initially rose in PC and RD rats but returned to CC levels by 12 h after removal from the pedestal. Predictably cortactin protein levels were initially unchanged but were up-regulated after 12 h. The PC group had more total and tyrosine-phosphorylated cortactin protein expression than the RD and CC groups. This increase in cortactin was likely due to the exposure of the rats to the novel environment of the deprivation chambers thus triggering plasticity events. The lack of REMS, however, severely hampered cortactin protein up-regulation and phosphorylation observed in the PC group suggesting an attenuation of plasticity-related events. Thus, these data support a functional link between REMS and cytoskeletal reorganization in the hippocampus, a process that is essential for synaptic plasticity.

Actins↗

PubMed2006

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity.

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.

Analysis of Variance↗

PubMed2005

Roles of brain angiotensins II and III in thirst and sodium appetite.

The current study examined the effects of intracerebroventricular (icv) infused aminopeptidase-resistant analogs of angiotensin II (AngII) and angiotensin III (AngIII) on thirst and sodium appetite. The analogs, [D-Asp1D-Arg2]AngII and [D-Arg1]AngIII, were further protected from degradation by pretreatment with the aminopeptidase A inhibitor, EC33, or the aminopeptidase N inhibitor, PC18. Prior to icv infusions, rats were sodium depleted with furosemide, followed by the angiotensin-converting enzyme inhibitor captopril, to block endogenous angiotensin formation. Both angiotensin analogs, at either of the two doses, were capable of eliciting fluid intakes of water and 0.3 M NaCl. Water and saline intakes were increased to a similar extent by 125 and 1250 pmol of [D-Asp1D-Arg2]AngII. [D-Arg1]AngIII produced a dose-dependent increase in water intake, whereas saline intake was equivalently increased by the 125 and 1250 pmol infusions. Pretreatment with EC33 or PC18 decreased water and saline intakes in response to [D-Asp1D-Arg2]AngII, while pretreatment with PC18 altered the time course of the [D-Arg1]AngIII-induced water and saline intakes. The ability of both inhibitors to decrease, but not completely block, AngII analog-induced intakes, coupled with the altered time course of the responses induced by the AngIII analog in the presence of PC18, supports the hypothesis that both AngII and AngIII are active ligands in brain angiotensin-mediated thirst and sodium appetite. However, these results do not resolve the primary question of whether conversion of AngII to AngIII is a prerequisite to dipsogenic and salt appetite responses in the brain.

Angiotensin II↗

PubMed2005

Role of mitogen-activated protein kinases during recovery from head-shake response habituation in rats.

Habituation is defined as a decrease in responsiveness to a repeatedly presented stimulus. The head-shake response (HSR) consists of a rapid twisting of the head about the front-to-rear axis elicited by a stream of air to the ear. This response demonstrates several fundamental properties of habituation including sensitivity to the frequency and intensity of stimulation, and spontaneous recovery. Despite an abundance of behavioral data on the HSR, relatively little is known about its physiological mechanism(s). To address this issue, changes in mitogen-activated protein kinases (MAPK) were assessed 5 min and 2, 6, and 24 h following the habituation of the HSR. Three cascades of MAPK activity were measured in the cerebellum and hippocampal, prefrontal, and piriform cortices, including extracellular-response kinase (ERK), p-38 kinase (p-38), and stress-activated protein kinase (SAPK). Significant activation of p-38 and SAPK was observed in all four brain structures, accompanied by modest changes in ERK activity. Recovery of the HSR was characterized by decreasing MAPK activation with control levels re-established 24 h after habituation. The present results suggest that MAPK activation mediates recovery from habituation; however, these findings may also support alternative interpretations such that MAPK activation reflects the encoding of spatial cues associated with the testing environment and/or are due to stress induced by the habituation protocol.

Animals↗

PubMed2004

Influence of hippocampectomy on habituation, exploratory behavior, and spatial memory in rats.

Two frequently cited functions of the hippocampus are mediation of spatial memories and habituation. The present investigation employed head-shake response (HSR) as the habituated behavior in intact and bilaterally hippocampectomized rats. This HSR appears to be minimally influenced by spatial cues. These rats were further tested on two behavioral paradigms that make use of spatial cues, namely open field object exploration, and the Morris water maze. The results indicate that hippocampectomized rats revealed habituation of the HSR, but not to objects within the open field. In agreement with previous reports, hippocampectomized rats were severely impaired both in acquiring and recalling the location of the submerged platform in the Morris water maze task. In a separate experiment independent groups of rats were trained on one of these three paradigms, and tissues were collected from hippocampal, prefrontal, and piriform cortices for the measurement of matrix metalloproteinases (MMPs) as markers of neural plasticity. There were significant MMP-9 elevations in the prefrontal and piriform cortices of rats tested using the object exploration task, in the prefrontal and hippocampal cortices of rats that solved the Morris water maze task, but minimal MMP changes in any tissues taken from HSR habituated rats. These results question the hypothesis that habituation is solely mediated by the hippocampus in favor of a process that utilizes different brain structures and degrees of neural plasticity dependent upon task requirements.

Animals↗

PubMed2004

Pharmacokinetic factors in sex differences in Delta 9-tetrahydrocannabinol-induced behavioral effects in rats.

Cannabinoids have been shown to produce greater behavioral effects in female than in male rats. Sex differences in the metabolism of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) have also been demonstrated in one study. The goal of this study was to determine if sex differences in Delta(9)-THC disposition or metabolism could explain sex differences in Delta(9)-THC-induced behavioral effects. [(3)H]-Delta(9)-THC was administered intraperitoneally (i.p.) to rats and the presence of [(3)H]-Delta(9)-THC and metabolites in serum and brain tissue were compared at multiple times post-injection in male versus female rats. Serum levels of Delta(9)-THC and its metabolites were similar in males and females. In brain tissue, [(3)H]-Delta(9)-THC levels also were similar in males and females. In contrast, levels of Delta(9)-THC metabolites in brain tissue, including 11-hydroxy-Delta(9)-THC, the major active metabolite, were higher in females than in males. To further investigate if greater production of active metabolites by females explained the greater Delta(9)-THC-induced behavioral effects observed in females, i.p. Delta(9)-THC-induced antinociception (50 degrees C warm water tail withdrawal assay) and catalepsy (bar test) were compared in male and female rats following pretreatment with saline or SKF525A, a cytochrome P450 inhibitor. SKF525A did not affect basal responding in the tail withdrawal assay or bar test in either sex. SKF525A significantly attenuated Delta(9)-THC-induced antinociception only in females. A similar sex difference was observed in the effects of SKF525A on Delta(9)-THC-induced catalepsy. These results suggest that the greater levels of active Delta(9)-THC metabolites produced by females contribute to greater behavioral effects of Delta(9)-THC in female compared to male rats.

Analgesics, Non-Narcotic↗

PubMed2004

Attenuation of scopolamine-induced learning deficits by LVV-hemorphin-7 in rats in the passive avoidance and water maze paradigms.

Central administration of angiotensin IV (Ang IV) analogues attenuates scopolamine-induced amnesia. Ang IV mediates its effects by binding to a high affinity, binding site, AT(4) receptor, that has recently been identified as insulin regulated aminopeptidase (IRAP). The purpose of this study was to examine the effect of the distinct AT(4) ligand, LVV-hemorphin-7 (LVV-H7), on scopolamine-induced learning deficits, one which involves fear-conditioning and the other spatial learning. Rats were pretreated with an intracerebroventricular (ICV) dose of scopolamine hydrobromide followed by treatment with 1 nmol LVV-H7 or artificial cerebrospinal fluid (aCSF). During the acquisition phase of the water maze task, daily ICV infusions of 1 nmol of LVV-H7 25 min after scopolamine treatment produced marked improvement in both the latency and distance swum in order to locate the submerged platform using visual cues compared to animals treated with scopolamine only. In addition, the same dose of LVV-H7 attenuated the learning deficit observed for scopolamine-treated animals in the passive avoidance task. These studies clearly demonstrate that LVV-H7, like Ang IV, is a pharmacologically active AT(4) ligand that attenuates the deleterious effects of scopolamine on learning performance in two different behavioral paradigms.

Aminopeptidases↗

PubMed2004

AT4 receptor binding in the developing rabbit.

The binding of the AT(4)-specific analog, divalinal-AngIV (Dival), was studied in rabbit fetuses of various gestational ages. Saturation isotherm and competition data from selected tissues indicate that fetal Dival binding sites are saturable and specific for AT(4) ligands. Autoradiographs revealed that binding was present in all the specimens examined. The peripheral nerves, kidneys, and heart were particularly heavily labeled. Labeling of some tissues, such as forming bones, was not constant as gestational age increased. Other tissues, including multilocular fat, sinus hairs, and enamel organs of nascent teeth, exhibited substantial binding as these tissues developed.

Angiotensin II↗

PubMed2004

Norleucine1-Angiotensin IV alleviates mecamylamine-induced spatial memory deficits.

The brain angiotensin AT4 receptor subtype has been implicated in cognitive processing. We initially established that intracerebroventricular administration of the nAChR-antagonist mecamylamine (mec) interfered with spatial memory performance in male Sprague-Dawley rats. Next we demonstrated that mec-induced deficits in spatial memory were overcome by the AT4 receptor-agonist Norleucine1-Angiotensin IV (Nle1-Ang IV). Nle1-Ang IV could not, however, compensate for spatial learning impairments precipitated by both mec and the mAChR-antagonist scopolamine. These findings support the importance of the AT4 receptor in cognitive processing and suggest that the ability of Nle1-Ang IV to improve spatial memory deficiencies may be dependant upon the brain cholinergic system.

Angiotensin II↗

PubMed2004

The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory.

The brain renin-angiotensin system (RAS) has long been known to regulate several classic physiologies including blood pressure, sodium and water balance, cyclicity of reproductive hormones and sexual behaviors, and pituitary gland hormones. These physiologies are thought to be under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AT2 receptor subtype is expressed during fetal development and is less abundant in the adult. This receptor appears to oppose growth responses facilitated by the AT1 receptor, as well as growth factor receptors. Recent evidence points to an important contribution by the brain RAS to non-classic physiologies mediated by the newly discovered angiotensin IV (AngIV)/AT4 receptor subtype system. These physiologies include the regulation of blood flow, modulation of exploratory behavior, and a facilitory role in learning and memory acquisition. This system appears to interact with brain matrix metalloproteinases in order to modify extracellular matrix molecules thus permitting the synaptic remodeling critical to the neural plasticity presumed to underlie memory consolidation, reconsolidation, and retrieval. There is support for an inhibitory influence by AngII activation of the AT1 subtype, and a facilitory role by AngIV activation of the AT4 subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning. The discovery of the AT4 receptor subtype, and its facilitory influence upon learning and memory, suggest an important role for the brain RAS in normal cognitive processing and perhaps in the treatment of dysfunctional memory disease states.

Animals↗

PubMed2003

REM sleep deprivation-induced deficits in the latency-to-peak induction and maintenance of long-term potentiation within the CA1 region of the hippocampus.

Sleep loss adversely affects certain types of cognitive processing, particularly associative memory. Given that long-term potentiation (LTP) represents a putative cellular basis of learning and memory consolidation, the influence of sleep deprivation on LTP was examined. Rats were REM sleep deprived for 24, 48, or 72 h using the inverted flowerpot method in temperature-regulated chambers. Hippocampal slices taken from sleep-deprived rats were compared with home cage and pedestal control animals at 5, 15 and 60 min post-tetanization. The results indicated that at 5 min post-tetanization there were no differences in field potentials in any of the sleep-deprived or control groups, suggesting comparable levels of induction. However, analysis of latency-to-peak slope indicated that members of the 48 and 72 h sleep-deprived groups required approximately twice as long to achieve maximum slope as the 24 h group, home cage or 24, 48, 72 h pedestal controls (means 8.17, 7.50, 2.67, 4.67 and 3.17 min, respectively). At 15 min post-tetanization there were no group differences, however at 60 min post-tetanization the slopes of the field excitatory postsynaptic potentials were significantly diminished for the 24, 48 and 72 h sleep-deprived groups (means 30.44, -1.89, 1.47, respectively) as compared with home cage and pedestal controls (means 59.54, 58.42, respectively). This delay in maximal induction, and the degradation of the maintenance phase of LTP, may represent sleep deprivation-induced impairment of the underlying neurochemical mechanisms normally responsible for memory acquisition.

Animals↗

PubMed2003

Ethanol-induced suppression of LTP can be attenuated with an angiotensin IV analog.

Hippocampal slices taken from animals chronically or acutely treated with ethanol exhibit significant inhibition of long-term potentiation (LTP). This inhibition appears to be associated with impaired activity of N-methyl-D-aspartate (NMDA) receptors, perhaps via ethanol-induced increases in GABAergic synaptic transmission. Recently, a role for the octapeptide angiotensin II (AngII) in ethanol's inhibition of LTP has been reported. Complementary to these findings our laboratory has shown that the application of the hexapeptide metabolite of AngII, angiotensin IV (AngIV), significantly facilitated normal tetanic-induced LTP in the hippocampal slice. This facilitation is presumably by activation of the angiotensin receptor subtype, AT(4). The present study tested whether an AT(4) receptor agonist could overcome ethanol-induced suppression of LTP. The results indicate that Nle(1)-AngIV could offset ethanol-induced suppression of LTP in the CA(1) region of the hippocampus. Pretreatment with the specific AT(4) receptor antagonist Nle(1), Leual(3)-AngIV blocked this facilitation implicating the involvement of the AT(4) receptor subtype. These results suggest that an AT(4) receptor agonist is effective in overcoming ethanol's suppressing influence on LTP, and encourage further investigation of the cognitive enhancing properties of such compounds.

Angiotensin II↗

PubMed2003

Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases.

The formation of spatial memory appears to be dependent upon an intact hippocampus capable of the specific biochemical changes associated with synaptic remodeling. Hippocampal damage results in the disruption of synaptic remodeling and the acquisition of spatial memory tasks. Ethanol also disrupts normal hippocampal functioning and spatial memory. The present investigation established a dose-response relationship between ethanol treatment and impairment of spatial memory as measured using the circular water maze task. Intraperitoneal ethanol doses of 1.5 and 2 g/kg significantly increased the latency and distance swam to find the submerged pedestal as compared with a 1 g/kg dose, and 0.15 M NaCl vehicle control treatments. On days 2, 4, and 6 of acquisition animals were sacrificed and brain tissues were retained from the hippocampus, prefrontal neocortex, and cerebellum for measurement of matrix metalloproteinases (MMPs). The results indicated that ethanol treatment interfered with MMP-9, but not MMP-2, activity in the hippocampus, and to a lesser degree in the prefrontal cortex. No changes in the cerebellum were measured. Elevations in MMP activity appear to be a prerequisite to reconfiguration of extracellular matrix cell adhesion molecules thought to be important in the process of synaptic plasticity, which in turn appears to be necessary for memory consolidation. Thus, ethanol-induced impairment in the acquisition of spatial memory tasks may, in part, be due to disruption of brain MMP activity.

Animals↗

PubMed2002

Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats.

The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp(1)ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.

Aminopeptidases↗

PubMed2002

Neural plasticity and the brain renin-angiotensin system.

The brain renin-angiotensin system mediates several classic physiologies including body water balance, maintenance of blood pressure, cyclicity of reproductive hormones and sexual behaviors, and regulation of pituitary gland hormones. In addition, angiotensin peptides have been implicated in neural plasticity and memory. The present review initially describes the extracellular matrix (ECM) and the roles of cell adhesion molecules (CAMs), matrix metalloproteinases, and tissue inhibitors of metalloproteinases in the maintenance and degradation of the ECM. It is the ECM that appears to permit synaptic remodeling and thus is critical to the plasticity that is presumed to underlie mechanisms of memory consolidation and retrieval. The interrelationship among long-term potentiation (LTP), CAMs, and synaptic strengthening is described, followed by the influence of angiotensins on LTP. There is strong support for an inhibitory influence by angiotensin II (AngII) and a facilitory role by angiotensin IV (AngIV), on LTP. Next, the influences of AngII and IV on associative and spatial memories are summarized. Finally, the impact of sleep deprivation on matrix metalloproteinases and memory function is described. Recent findings indicate that sleep deprivation-induced memory impairment is accompanied by a lack of appropriate changes in matrix metalloproteinases within the hippocampus and neocortex as compared with non-sleep deprived animals. These findings generally support an important contribution by angiotensin peptides to neural plasticity and memory consolidation.

Animals↗

PubMed2002

Extracellular matrix molecules, long-term potentiation, memory consolidation and the brain angiotensin system.

Considerable evidence now suggests an interrelationship among long-term potentiation (LTP), extracellular matrix (ECM) reconfiguration, synaptogenesis, and memory consolidation within the mammalian central nervous system. Extracellular matrix molecules provide the scaffolding necessary to permit synaptic remodeling and contribute to the regulation of ionic and nutritional homeostasis of surrounding cells. These molecules also facilitate cellular proliferation, movement, differentiation, and apoptosis. The present review initially focuses on characterizing the ECM and the roles of cell adhesion molecules (CAMs), matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), in the maintenance and degradation of the ECM. The induction and maintenance of LTP is described. Debate continues over whether LTP results in some form of synaptic strengthening and in turn promotes memory consolidation. Next, the contribution of CAMs and TIMPs to the facilitation of LTP and memory consolidation is discussed. Finally, possible roles for angiotensins, MMPs, and tissue plasminogen activators in the facilitation of LTP and memory consolidation are described. These enzymatic pathways appear to be very important to an understanding of dysfunctional memory diseases such as Alzheimer's disease, multiple sclerosis, brain tumors, and infections.

Angiotensins↗